Effects of a topical treatment with spleen tyrosine kinase inhibitor in healthy subjects and patients with cold urticaria or chronic spontaneous urticaria: Results of a phase 1a/b randomised double‐blind placebo‐controlled study

• Published in: British journal of clinical pharmacology Vol. 87; no. 12; pp. 4797 - 4808
• Main Authors: Dickson, Marion C., Walker, Alexandra, Grattan, Clive, Perry, Hayley, Williams, Nicola, Ratia, Nirav, Dewit, Odile, Gisbert, Sophie, Metz, Martin, Maurer, Marcus
• Format: Journal Article
• Language: English
• Published: England 01.12.2021
• Subjects: Chronic Disease; chronic spontaneous urticaria; Chronic Urticaria; cold urticaria; Healthy Volunteers; Humans; Protein Kinase Inhibitors - therapeutic use; skin allergen challenge; Spleen; spleen tyrosine kinase; TempTest; Urticaria - drug therapy; skin allergen challenge; cold urticaria; spleen tyrosine kinase; TempTest; chronic spontaneous urticaria
• ISSN: 0306-5251; 1365-2125; 1365-2125
• DOI: 10.1111/bcp.14923

Aims To explore the safety, tolerability, pharmacokinetics and pharmacodynamics (PD) of GSK2646264 using skin challenge models. Methods Healthy volunteers (HV) with a positive allergen skin prick test received GSK2646264 (0.5% or 1% ww) and placebo creams on up to 10% body surface area (BSA). Cold (ColdU) or chronic spontaneous (CSU) urticaria patients received 1% GSK2646264 or placebo on up to 10% BSA. PD assessments included weal characteristics after skin allergen challenge, critical temperature threshold (CTT) in ColdU patients and defined area urticaria activity score in CSU patients. Results Thirty‐four patients were randomised (17 HV, 12 ColdU, 5 CSU). Topical application of GSK2646264 and placebo was well tolerated. Systemic pharmacokinetics (AUC [0–24] h*ng/mL) was similar between HVs (Geomean 97.9 [%CV 37]) and ColdU patients (Geomean 68.2 [%CV 14; 3.5% BSA] or 167 [%CV 120; 10% BSA]). Whilst in HVs a similar reduction in skin allergen challenge weal area was observed following 3 applications of GSK2646264 and placebo, a trend towards a greater reduction was seen in ColdU with GSK2646264 compared to placebo. A clinically meaningful reduction in CTT, in ColdU patients treated with GSK2646264, was observed in 4 of 9 patients, who demonstrated either a complete inhibition of ColdU to ≤4°C (n = 2) or partial response (reduction by >4°C, n = 2). Due to the small number of CSU patients recruited, no meaningful conclusions could be drawn from the defined area urticaria activity score PD endpoint. Conclusion This Phase 1/1b study confirms that GSK2646264 cream applied topically penetrates the skin and some reduction in CTT was observed. (NCT02424799)